4-49061855-C-A

Variant names:

• chr4-49061855-C-A
• rs1051447
• NM_025087.3:c.2065C>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_025087.3(CWH43):​c.2065C>A​(p.His689Asn) variant causes a missense change. The variant allele was found at a frequency of 0.655 in 1,355,700 control chromosomes in the GnomAD database, including 304,566 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.58 (28780 hom., cov: 32)
  • Exomes 𝑓: 0.66 (275786 hom.)
• Consequence: CWH43 NM_025087.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.07
• Publications: 36 publications found

Genes affected

CWH43 (HGNC:26133): (cell wall biogenesis 43 C-terminal homolog) Predicted to be involved in GPI anchor biosynthetic process. Predicted to be integral component of membrane. Predicted to be active in endoplasmic reticulum. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.6461898E-6).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.737 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_025087.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CWH43	NM_025087.3	MANE Select	c.2065C>A	p.His689Asn	missense	Exon 16 of 16	NP_079363.2	Q9H720
	CWH43	NM_001286791.2		c.1984C>A	p.His662Asn	missense	Exon 16 of 16	NP_001273720.1	E7EQL2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CWH43	ENST00000226432.9	TSL:1 MANE Select	c.2065C>A	p.His689Asn	missense	Exon 16 of 16	ENSP00000226432.4	Q9H720
	CWH43	ENST00000856986.1		c.2122C>A	p.His708Asn	missense	Exon 16 of 16	ENSP00000527045.1
	CWH43	ENST00000856987.1		c.2050C>A	p.His684Asn	missense	Exon 16 of 16	ENSP00000527046.1

Frequencies

GnomAD3 genomes AF: 0.580 AC: 88083 AN: 151770 Hom.: 28775 Cov.: 32

Gnomad AFR AF: 0.268

Gnomad AMI AF: 0.744

Gnomad AMR AF: 0.748

Gnomad ASJ AF: 0.743

Gnomad EAS AF: 0.385

Gnomad SAS AF: 0.522

Gnomad FIN AF: 0.731

Gnomad MID AF: 0.747

Gnomad NFE AF: 0.715

Gnomad OTH AF: 0.645

GnomAD2 exomes AF: 0.652 AC: 109027 AN: 167110 AF XY: 0.659

Gnomad AFR exome AF: 0.237

Gnomad AMR exome AF: 0.792

Gnomad ASJ exome AF: 0.728

Gnomad EAS exome AF: 0.354

Gnomad FIN exome AF: 0.739

Gnomad NFE exome AF: 0.718

Gnomad OTH exome AF: 0.692

GnomAD4 exome AF: 0.665 AC: 800303 AN: 1203812 Hom.: 275786 Cov.: 27 AF XY: 0.663 AC XY: 394448 AN XY: 595210

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.234 AC: 6073 AN: 25912

American (AMR) AF: 0.763 AC: 13863 AN: 18164

Ashkenazi Jewish (ASJ) AF: 0.717 AC: 14120 AN: 19696

East Asian (EAS) AF: 0.347 AC: 10516 AN: 30316

South Asian (SAS) AF: 0.531 AC: 33370 AN: 62896

European-Finnish (FIN) AF: 0.713 AC: 28744 AN: 40334

Middle Eastern (MID) AF: 0.747 AC: 3631 AN: 4862

European-Non Finnish (NFE) AF: 0.692 AC: 659215 AN: 952854

Other (OTH) AF: 0.631 AC: 30771 AN: 48778

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.580 AC: 88114 AN: 151888 Hom.: 28780 Cov.: 32 AF XY: 0.582 AC XY: 43191 AN XY: 74248

African (AFR) AF: 0.267 AC: 11078 AN: 41422

American (AMR) AF: 0.748 AC: 11428 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.743 AC: 2576 AN: 3466

East Asian (EAS) AF: 0.386 AC: 1990 AN: 5158

South Asian (SAS) AF: 0.524 AC: 2525 AN: 4818

European-Finnish (FIN) AF: 0.731 AC: 7679 AN: 10498

Middle Eastern (MID) AF: 0.741 AC: 218 AN: 294

European-Non Finnish (NFE) AF: 0.715 AC: 48591 AN: 67944

Other (OTH) AF: 0.642 AC: 1352 AN: 2106

Alfa AF: 0.665 Hom.: 88422

Bravo AF: 0.573

TwinsUK AF: 0.697 AC: 2584

ALSPAC AF: 0.702 AC: 2704

ESP6500AA AF: 0.276 AC: 1204

ESP6500EA AF: 0.713 AC: 6045

ExAC AF: 0.648 AC: 78532

Asia WGS AF: 0.460 AC: 1590 AN: 3448

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.52
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0072	T
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.50	T
MetaRNN	Benign	0.0000017	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		4.1
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-1.8	N
REVEL	Benign	0.082
Sift	Benign	0.37	T
Sift4G	Uncertain	0.019	D
Polyphen		0.96	D
Vest4		0.24
MPC		0.16
ClinPred		0.031	T
GERP RS		4.6
Varity_R		0.21
gMVP		0.49
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1051447; hg19: chr4-49063872; COSMIC: COSV56936745;